highlights of prescribing information ......9/l, resume nplate at a dose reduced by 1 mcg/kg....
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NPLATE safely and effectively. See full prescribing information for
NPLATE.
NPLATE® (romiplostim) for injection, for subcutaneous use
Initial U.S. Approval: 2008
----------------------------INDICATIONS AND USAGE---------------------------
Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP)
who have had an insufficient response to corticosteroids, immunoglobulins, or
splenectomy.
Limitations of Use:
Nplate is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia
other than chronic ITP.
Nplate should be used only in patients with ITP whose degree of
thrombocytopenia and clinical condition increases the risk for bleeding.
Nplate should not be used in an attempt to normalize platelet counts. (1)
----------------------DOSAGE AND ADMINISTRATION----------------------
Initial dose of 1 mcg/kg once weekly as a subcutaneous injection. (2.1)
Adjust weekly dose by increments of 1 mcg/kg to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding.
(2.1)
Do not exceed the maximum weekly dose of 10 mcg/kg. Do not dose if
platelet count is > 400 x 109/L. (2.1)
Discontinue Nplate if platelet count does not increase after 4 weeks at the maximum dose. (2.1)
Do not shake during reconstitution; protect reconstituted Nplate from light; administer reconstituted Nplate within 24 hours. (2.2)
The injection volume may be very small. Use a syringe with graduations to 0.01 mL. (2.2)
Discard any unused portion of the single-dose vial. (2.2)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
For injection: 250 mcg or 500 mcg of deliverable romiplostim as a
lyophilized powder in single-dose vials (3).
-------------------------------CONTRAINDICATIONS ---------------------------None (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
In some patients with MDS, Nplate increases blast cell counts and
increases the risk of progression to acute myelogenous leukemia. (5.1)
Thrombotic/thromboembolic complications may result from increases in
platelet counts with Nplate use. Portal vein thrombosis has been
reported in patients with chronic liver disease receiving Nplate. (5.2)
If severe thrombocytopenia develops during Nplate treatment, assess
patients for the formation of neutralizing antibodies. (5.3)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions (≥ 5% higher patient incidence in Nplate versus placebo) are arthralgia, dizziness, insomnia, myalgia, pain in extremity,
abdominal pain, shoulder pain, dyspepsia, and paresthesia. Headache was the
most commonly reported adverse reaction that did not occur at ≥ 5% higher patient incidence in Nplate versus placebo. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at
1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-----------------------------USE IN SPECIFIC POPULATIONS-----------------
Pregnancy: Based on animal data, Nplate may cause fetal harm. (8.1)
Nursing Mothers: A decision should be made to discontinue Nplate or
nursing, taking into account the importance of Nplate to the mother. (8.3)
See 17 FOR PATIENT COUNSELING INFORMATION AND
Medication Guide
Revised: 4/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage Regimen
2.2 Preparation and Administration 2.3 Use of Nplate With Concomitant Medical ITP Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Progression of Myelodysplastic Syndromes to Acute
Myelogenous Leukemia 5.2 Thrombotic/Thromboembolic Complications
5.3 Loss of Response to Nplate
5.4 Laboratory Monitoring
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience 6.3 Immunogenicity
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers 8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment 8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics 12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Chronic ITP
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
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1
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
Nplate is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP)
who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.
Limitations of use:
Nplate is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any
cause of thrombocytopenia other than chronic ITP [see Warnings and Precautions (5.1)].
Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition
increases the risk for bleeding [see Warnings and Precautions (5.2)].
Nplate should not be used in an attempt to normalize platelet counts [see Warnings and Precautions (5.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage Regimen
Use the lowest dose of Nplate to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk
for bleeding. Administer Nplate as a weekly subcutaneous injection with dose adjustments based upon the platelet count response.
The prescribed Nplate dose may consist of a very small volume (eg, 0.15 mL). Administer Nplate only with a syringe that contains 0.01 mL graduations.
Initial Dose The initial dose for Nplate is 1 mcg/kg based on actual body weight.
Dose Adjustments Use the actual body weight at initiation of therapy, then adjust the weekly dose of Nplate by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 x 10
9/L as necessary to reduce the risk for bleeding; do not exceed a
maximum weekly dose of 10 mcg/kg. In clinical studies, most patients who responded to Nplate achieved and maintained platelet counts ≥ 50 x 10
9/L with a median dose of 2 mcg/kg.
During Nplate therapy, assess CBCs, including platelet counts, weekly until a stable platelet count (≥ 50 x 109/L for
at least 4 weeks without dose adjustment) has been achieved. Obtain CBCs, including platelet counts, monthly thereafter.
Adjust the dose as follows:
If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
If platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
If platelet count is > 400 x 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet
count has fallen to < 200 x 109/L, resume Nplate at a dose reduced by 1 mcg/kg.
Discontinuation
Discontinue Nplate if the platelet count does not increase to a level sufficient to avoid clinically important bleeding
after 4 weeks of Nplate therapy at the maximum weekly dose of 10 mcg/kg [see Warnings and Precautions (5.3)].
Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate [ see
Warnings and Precautions (5.4)].
2.2 Preparation and Administration
To mitigate against medication errors (both overdose and underdose), ensure that these preparation and
administration instructions are followed.
Calculate the dose and reconstitute with the correct volume of sterile water for injection. Withdraw the appr opriate
volume of the calculated dose from the vial. Only administer subcutaneously [see Overdosage (10)].
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Nplate is supplied in single-dose vials as a sterile, preservative-free, white lyophilized powder that must be
reconstituted as outlined in Table 1 and administered using a syringe with 0.01 mL graduations. Using aseptic
technique, reconstitute Nplate with preservative-free Sterile Water for Injection, USP as described in Table 1. Do
not use bacteriostatic water for injection.
Table 1. Reconstitution of Nplate Single-Dose Vials
Nplate
Single-Dose Vial
Total Vial Content
of Nplate*
Sterile Water
for Injection**
Deliverable Product
and Volume
Final
Concentration
250 mcg 375 mcg add 0.72 mL = 250 mcg in 0.5 mL 500 mcg/mL
500 mcg 625 mcg add 1.2 mL = 500 mcg in 1 mL 500 mcg/mL * Total vial content includes overfill to ensure delivery of 250 mcg or 500 mcg ** Use preservative-free Sterile Water for Injection.
Gently swirl and invert the vial to reconstitute. Avoid excess or vigorous agitation: DO NOT SHAKE. Generally, dissolution of Nplate takes less than 2 minutes. The reconstituted Nplate solution should be clear and colorless. Visually inspect the reconstituted solution for particulate matter and/or discoloration. Do not administer Nplate if particulate matter and/or discoloration is observed.
Reconstituted Nplate can be kept at room temperature (25°C/77°F) or refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours prior to administration. Protect the reconstituted product from light.
To determine the injection volume to be administered, first identify the patient’s total dose in micrograms (mcg)
using the dosing information in Section 2.1. For example, a 75 kg patient initiating therapy at 1 mcg/kg will begin
with a dose of 75 mcg. Next, calculate the volume of Nplate solution that is given to the patient by dividing the
microgram dose by the concentration of the reconstituted Nplate solution (500 mcg/mL). For this patient example,
the 75 mcg dose is divided by 500 mcg/mL, resulting in an injection volume of 0.15 mL.
As the injection volume may be very small, use a syringe with graduations to 0.01 mL. Verify that the syringe
contains the correct dosage.
Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than one dose
from a vial.
2.3 Use of Nplate With Concomitant Medical ITP Therapies
Nplate may be used with other medical ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous
immunoglobulin (IVIG), and anti-D immunoglobulin. If the patient’s platelet count is ≥ 50 x 109/L, medical ITP
therapies may be reduced or discontinued [see Clinical Studies (14.1)].
3 DOSAGE FORMS AND STRENGTHS
For injection: 250 mcg or 500 mcg of deliverable romiplostim as a sterile, lyophilized, solid white powder in single-
dose vials.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia
Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in
clinical trials with Nplate. A randomized, double-blind, placebo-controlled trial enrolling patients with severe
thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was
terminated due to more cases of AML observed in the Nplate treatment arm. At the time of an interim analysis,
among 219 MDS patients randomized 2:1 to treatment with Nplate or placebo (147 Nplate: 72 placebo),
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11 patients showed progression to AML, including nine on the Nplate arm versus two on the placebo arm. In
addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28
patients, 25 of whom were in the romiplostim treatment arm. Of the 28 patients who had an increase in circulating
myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML and 20 patients had not
progressed to AML. In four patients, increased peripheral blood blast cell counts decreased to baseline after
discontinuation of Nplate. In a single-arm trial of Nplate given to 72 patients with thrombocytopenia related to
MDS, eight (11%) patients were reported as having possible disease progression, and three patients had
confirmation of AML during follow-up. In addition, in three patients, increased peripheral blood blast cell counts
decreased to baseline after discontinuation of Nplate.
Nplate is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other
than chronic ITP.
5.2 Thrombotic/Thromboembolic Complications
Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate use. Portal vein
thrombosis has been reported in patients with chronic liver disease receiving Nplate.
To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate in an attempt to normalize
platelet counts. Follow the dose adjustment guidelines [see Dosage and Administration (2.1)].
5.3 Loss of Response to Nplate
Hyporesponsiveness or failure to maintain a platelet response with Nplate should prompt a search for causative
factors, including neutralizing antibodies to Nplate [see Adverse Reactions (6.3)]. To detect antibody formation,
submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate and
thrombopoietin (TPO). Discontinue Nplate if the platelet count does not increase to a level sufficient to avoid
clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
5.4 Laboratory Monitoring
Obtain CBCs, including platelet counts, weekly during the dose-adjustment phase of Nplate therapy and then
monthly following establishment of a stable Nplate dose. Obtain CBCs, including platelet counts, weekly for at
least 2 weeks following discontinuation of Nplate [see Dosage and Administration (2.1)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections: Progression of Myelodysplastic Syndromes [see Warnings and Precautions (5.1)] Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.2)] Loss of Response to Nplate [see Warnings and Precautions (5.3)] Laboratory Monitoring [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
The data described below reflect Nplate exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62%
were female. Nplate was studied in two randomized, placebo-controlled, double-blind studies that were identical in
design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated
splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients
received Nplate over an extended period of time. Overall, Nplate was administered to 114 patients for at least
52 weeks and 53 patients for at least 96 weeks.
In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in
35% of patients receiving Nplate and 32% of patients receiving placebo. Headaches were usually of mild or
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moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5% higher patient
incidence in Nplate versus placebo. The majority of these adverse drug reactions were mild to moderate in severity.
Table 2. Adverse Drug Reactions Identified in Two Placebo-Controlled Studies
Preferred Term Nplate
(n = 84)
Placebo
(n = 41)
Arthralgia 26% 20%
Dizziness 17% 0%
Insomnia 16% 7%
Myalgia 14% 2%
Pain in Extremity 13% 5%
Abdominal Pain 11% 0%
Shoulder Pain 8% 0%
Dyspepsia 7% 0%
Paresthesia 6% 0%
Among 142 patients with chronic ITP who received Nplate in the single-arm extension study, the incidence rates of
the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies.
Bone Marrow Reticulin Formation and Collagen Fibrosis
Nplate administration may increase the risk for development or progression of reticulin fiber formation within the
bone marrow. This formation may improve upon discontinuation of Nplate. In a clinical trial, one patient with ITP
and hemolytic anemia developed marrow fibrosis with collagen during Nplate therapy.
An open-label clinical trial prospectively evaluated changes in bone marrow reticulin formation and collagen
fibrosis in adult patients with ITP treated with Nplate or a non-US approved romiplostim product. Patients were
administered romiplostim by SC injection once weekly for up to 3 years. Based on cohort assignment at time of
study enrollment, patients were evaluated for bone marrow reticulin and collagen at year 1 (cohort1), year 2 (cohort
2) or year 3 (cohort 3) in comparison to the baseline bone marrow at start of the trial. Patients were evaluated for
bone marrow reticulin formation and collagen fibrosis using the modified Bauermeister grading scale. From the total
of 169 patients enrolled in the 3 cohorts, 132 (78%) patients were evaluable for bone marrow collagen fibrosis, and
131 (78%) patients were evaluable for bone marrow reticulin formation. Two percent (2/132) of patients (both from
cohort 3) developed grade 4 findings (presence of collagen). There was no detectable bone marrow collagen in one
patient on repeat testing 12 weeks after discontinuation of romiplostim. Progression of bone marrow reticulin
formation (increase greater than or equal to 2 grades or more) or an increase to Grade 4 (presence of collagen) was
reported in 7% (9/131) of patients.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of Nplate. Because these reactions
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Erythromelalgia
Hypersensitivity
Angioedema
6.3 Immunogenicity
As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened
for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of
detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The
samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity
using a cell-based bioassay.
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In clinical studies in patients with ITP, the incidence of preexisting antibodies to romiplostim was 5% (53/1112) and
the incidence of binding antibody development during treatment with Nplate or a non-US approved romiplostim
product was 4% (50/1112). The incidence of preexisting antibodies to endogenous TPO was 4% (40/1112) and the
incidence of binding antibody development to endogenous TPO during treatment was 3% (38/1112). Of the patients
with positive binding antibodies that developed to romiplostim or to TPO, five patients had neutralizing activity to
romiplostim and none had neutralizing activity to TPO. No apparent correlation was observed between antibod y
activity and clinical effectiveness or safety.
A post marketing registry study involving patients with thrombocytopenia on Nplate or a non-US approved
romiplostim product was conducted to assess the long-term consequences of the anti-romiplostim antibodies.
Patients who lacked response or lost response to Nplate or a non-US approved romiplostim product were enrolled.
The incidence of new binding antibody development was 3% (5/186) to romiplostim and 1% (2/186) to TPO. One
patient was positive for binding antibodies to both romiplostim and TPO. Of the five patients with positive binding
antibodies to romiplostim, two (1%) were positive for neutralizing antibodies to romiplostim only.
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection
and may be influenced by several factors, including sample handling, concomitant medications, and underlying
disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to
other products may be misleading.
7 DRUG INTERACTIONS
No formal drug interaction studies of Nplate have been performed.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Nplate use in pregnant women. In animal reproduction and
developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis,
postimplantation loss, and an increase in pup mortality. Nplate should be used during pregnancy only if the
potential benefit to the mother justifies the potential risk to the fetus.
In rat and rabbit developmental toxicity studies, no evidence of fetal harm was observed at romiplostim doses up to
11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at
doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred.
In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal
pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically
equivalent and higher doses.
Women who become pregnant during Nplate treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance
Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
8.3 Nursing Mothers
It is not known whether Nplate is excreted in human milk; however, human IgG is excreted in human milk.
Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in s ubstantial
amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions
in nursing infants from Nplate, a decision should be made whether to discontinue nursing or to discontinue Nplate,
taking into account the importance of Nplate to the mother and the known benefits of nursing.
8.4 Pediatric Use
The safety and effectiveness in pediatric patients (< 18 years) have not been established.
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8.5 Geriatric Use
Of the 271 patients who received Nplate in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were
75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in
the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose
adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
8.6 Renal Impairment
No clinical studies were conducted in patients with renal impairment.
8.7 Hepatic Impairment
No clinical studies were conducted in patients with hepatic impairment.
10 OVERDOSAGE
Overdoses due to medication errors have been reported in patients receiving Nplate. In the event of overdose,
platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case,
discontinue Nplate and monitor platelet counts. Reinitiate treatment with Nplate in accordance with dosing and
administration recommendations [see Dosage and Administration (2.1, 2.2)].
11 DESCRIPTION
Romiplostim, a member of the TPO mimetic class, is an Fc-peptide fusion protein (peptibody) that activates
intracellular transcriptional pathways leading to increased platelet production via the TPO receptor (also known as
cMpl). The peptibody molecule contains two identical single-chain subunits, each consisting of human
immunoglobulin IgG1 Fc domain, covalently linked at the C-terminus to a peptide containing two thrombopoietin
receptor-binding domains. Romiplostim has no amino acid sequence homology to endogenous TPO. Romiplostim
is produced by recombinant DNA technology in Escherichia coli (E coli).
Nplate is supplied as a sterile, preservative-free, lyophilized, solid white powder for subcutaneous injection. Two
vial presentations are available, which contain a sufficient amount of active ingredient to provide either 250 mcg or
500 mcg of deliverable romiplostim, respectively. Each single-dose 250 mcg vial of Nplate contains the following:
375 mcg romiplostim, 30 mg mannitol, 15 mg sucrose, 1.2 mg L-histidine, 0.03 mg polysorbate 20, and sufficient
HCl to adjust the pH to a target of 5.0. Each single-dose 500 mcg vial of Nplate contains the following: 625 mcg
romiplostim, 50 mg mannitol, 25 mg sucrose, 1.9 mg L-histidine, 0.05 mg polysorbate 20, and sufficient HCl to
adjust the pH to a target of 5.0 [see Dosage and Administration (2.2)].
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Nplate increases platelet production through binding and activation of the TPO receptor, a mechanism analogous to
endogenous TPO.
12.2 Pharmacodynamics
In clinical studies, treatment with Nplate resulted in dose-dependent increases in platelet counts. After a single
subcutaneous dose of 1 to 10 mcg/kg Nplate in patients with chronic ITP, the peak platelet count was 1.3 to 14.9
times greater than the baseline platelet count over a 2- to 3-week period. The platelet counts were above 50 x 109/L
for seven out of eight patients with chronic ITP who received six weekly doses of Nplate at 1 mcg/kg.
12.3 Pharmacokinetics
In the long-term extension study in patients with ITP receiving weekly treatment of Nplate subcutaneously, the
pharmacokinetics of romiplostim over the dose range of 3 to 15 mcg/kg indicated that peak serum concentrations of
romiplostim were observed about 7 to 50 hours post dose (median: 14 hours) with half-life values ranging from 1 to
34 days (median: 3.5 days). The serum concentrations varied among patients and did not correlate with the dose
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administered. The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a
result, for a given dose, patients with high platelet counts are associated with low serum concentrations and vice
versa. In another ITP clinical study, no accumulation in serum concentrations was observed (n = 4) after six weekly
doses of Nplate (3 mcg/kg). The accumulation at higher doses of romiplostim is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of romiplostim has not been evaluated. The mutagenic potential of romiplostim has not
been evaluated. Romiplostim had no effect on the fertility of rats at doses up to 37 times the MHD based on
systemic exposure.
13.2 Animal Toxicology and/or Pharmacology
In a 4-week repeat-dose toxicity study in which rats were dosed subcutaneously three times per week, romiplostim
caused extramedullary hematopoiesis, bone hyperostosis, and marrow fibrosis at clinically equivalent and higher
doses. In this study, these findings were not observed in animals after a 4-week post treatment recovery period.
Studies of long-term treatment with romiplostim in rats have not been conducted; therefore, it is not known if the
fibrosis of the bone marrow is reversible in rats after long-term treatment.
14 CLINICAL STUDIES
14.1 Chronic ITP
The safety and efficacy of Nplate were assessed in two double-blind, placebo-controlled clinical studies and in an
open-label extension study.
Studies 1 and 2
In Studies 1 and 2, patients with chronic ITP who had completed at least one prior treatment and had a platelet count
of ≤ 30 x 109/L prior to study entry were randomized (2:1) to 24 weeks of Nplate (1 mcg/kg subcutaneous [SC]) or
placebo. Prior ITP treatments in both study groups included corticosteroids, immunoglobulins, rituximab, cytotoxic
therapies, danazol, and azathioprine. Patients already receiving ITP medical therapies at a constant dosing schedule
were allowed to continue receiving these medical treatments throughout the studies. Rescue therapies
(ie, corticosteroids, IVIG, platelet transfusions, and anti-D immunoglobulin) were permitted for bleeding, wet
purpura, or if the patient was at immediate risk for hemorrhage. Patients received single weekly SC injections of
Nplate, with individual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 10
9/L).
Study 1 evaluated patients who had not undergone a splenectomy. The patients had been diagnosed with ITP for
approximately 2 years and had received a median of three prior ITP treatments. Overall, the median platelet count
was 19 x 109/L at study entry. During the study, the median weekly Nplate dose was 2 mcg/kg (25th–75th
percentile: 1–3 mcg/kg).
Study 2 evaluated patients who had undergone a splenectomy. The patients had been diagnosed with ITP for
approximately 8 years and had received a median of six prior ITP treatments. Overall, the median platelet count was
14 x 109/L at study entry. During the study, the median weekly Nplate dose was 3 mcg/kg (25th–75th
percentile: 2–7 mcg/kg).
Study 1 and 2 outcomes are shown in Table 3. A durable platelet response was the achieve ment of a weekly platelet
count ≥ 50 x 109/L for any 6 of the last 8 weeks of the 24-week treatment period in the absence of rescue medication
at any time. A transient platelet response was the achievement of any weekly platelet counts ≥ 50 x 10 9/L for any
4 weeks during the treatment period without a durable platelet response. An overall platelet response was the
achievement of either a durable or a transient platelet response. Platelet responses were excluded for 8 weeks after
receiving rescue medications.
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Table 3. Results From Placebo-Controlled Studiesa
Outcomes
Study 1
Nonsplenectomized Patients
Study 2
Splenectomized Patients
Nplate
(n = 41)
Placebo
(n = 21)
Nplate
(n = 42)
Placebo
(n = 21)
Platelet Responses and Rescue Therapy
Durable Platelet Response, n (%) 25 (61%) 1 (5%) 16 (38%) 0 (0%)
Overall Platelet Response, n (%) 36 (88%) 3 (14%) 33 (79%) 0 (0%)
Number of Weeks With Platelet Counts ≥
50 x 109/L, average
15 1 12 0
Requiring Rescue Therapy, n (%) 8 (20%) 13 (62%) 11 (26%) 12 (57%)
Reduction/Discontinuation of Baseline Concurrent ITP Medical Therapy
Receiving Therapy at Baseline (n = 11) (n = 10) (n = 12) (n = 6)
Patients Who Had > 25% Dose Reduction
in Concurrent Therapy, n (%) 4/11
(36%)
2/10
(20%)
4/12
(33%)
1/6
(17%)
Patients Who Discontinued Baseline
Therapy, n (%)b
4/11
(36%)
3/10
(30%)
8/12
(67%)
0/6
(0%) a All p values < 0.05 for platelet response and rescue therapy comparisons between Nplate and placebo. b For multiple concomitant baseline therapies, all therapies were discontinued.
In Studies 1 and 2, nine patients reported a serious bleeding event [five (6%) Nplate, four (10%) placebo]. Bleeding
events that were grade 2 severity or higher occurred in 15% of patients treated with Nplate and 34% of patients
treated with placebo.
Extension Study
Patients who had participated in either Study 1 or Study 2 were withdrawn from study medications. If platelet
counts subsequently decreased to ≤ 50 x 109/L, the patients were allowed to receive Nplate in an open-label
extension study with weekly dosing based on platelet counts. Following Nplate discontinuation in Studies 1 and 2,
seven patients maintained platelet counts of ≥ 50 x 109/L. Among 100 patients who subsequently entered the
extension study, platelet counts were increased and sustained regardless of whether they had received Nplate or
placebo in the prior placebo-controlled studies. The majority of patients reached a median platelet count of
50 x 109/L after receiving one to three doses of Nplate, and these platelet counts were maintained throughout the
remainder of the study with a median duration of Nplate treatment of 60 weeks and a maximum duration of
96 weeks.
16 HOW SUPPLIED/STORAGE AND HANDLING
Nplate is supplied in single-dose vials that deliver 250 mcg (NDC 55513-221-01) and 500 mcg (NDC 55513-222
01) of romiplostim.
Store Nplate vials in their carton to protect from light until time of use. Keep Nplate vials refrigerated at 2 to 8C
(36 to 46F). Do not freeze.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
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Information for Patients
Prior to treatment, patients should fully understand the risks and benefits of Nplate. Inform patients that the risks
associated with long-term administration of Nplate are unknown.
Inform patients of the following risks and considerations for Nplate:
Nplate therapy is administered to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce
the risk for bleeding; Nplate is not used to normalize platelet counts.
Following discontinuation of Nplate, thrombocytopenia and risk of bleeding may develop that is worse than
that experienced prior to the Nplate therapy.
Nplate therapy may increase the risk of reticulin fiber formation within the bone marrow. This formation
may improve upon discontinuation. Detection of peripheral blood cell abnormalities may necessitate a
bone marrow examination.
Too much Nplate may result in excessive platelet counts and a risk for thrombotic/thromboembolic
complications.
Nplate stimulates certain bone marrow cells to make platelets and increases the risk of progression to acute
myelogenous leukemia in patients with myelodysplastic syndromes.
Platelet counts and CBCs must be performed weekly until a stable Nplate dose has been achieved; thereafter, platelet counts and CBCs must be performed monthly while taking Nplate.
Patients must be closely monitored with weekly platelet counts and CBCs for at least 2 weeks following
Nplate discontinuation.
Even with Nplate therapy, patients should continue to avoid situations or medications that may increase the
risk for bleeding.
Nplate®
(romiplostim)
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
U.S. License No. 1080
Patent: http://pat.amgen.com/nplate/
© 2008-2016 Amgen Inc. All rights reserved.
www.nplate.com
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Reference ID: 3919389
10
MEDICATION GUIDE
Nplate®
(N-plāt)
(romiplostim)
Read this Medication Guide before you start Nplate and before each Nplate injection. There may be new
information. This Medication Guide does not take the place of talking to your healthcare provider about your
medical condition or your treatment.
What is the most important information I should know about Nplate?
Nplate can cause serious side effects, including:
Worsening of a precancerous blood condition to a blood cancer (leukemia). Nplate is not for use in people
with a precancerous condition called myelodysplastic syndromes (MDS) or for any condition other than chronic
(lasting a long time) immune thrombocytopenia (ITP). If you have MDS and receive Nplate, your MDS
condition may worsen and become an acute leukemia. If MDS worsens to become acute leukemia you may die
sooner from the acute leukemia.
Higher risk for blood clots.
o You may have a higher risk of getting a blood clot if your platelet count becomes high during treatment
with Nplate. You may have severe complications or die from some forms of blood clots, such as clots that
spread to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood
platelet counts and change your dose or stop Nplate if your platelet counts get high.
o If you have a chronic liver disease, you may get blood clots in the veins of your liver. This may affect your
liver function.
When you are being treated with Nplate, your healthcare provider will closely monitor your Nplate dose and blood
tests, including platelet counts.
Injection of too much Nplate may cause a dangerous increase in your blood platelet count and serious side
effects.
During Nplate therapy, your healthcare provider may change your Nplate dose, depending upon the change in
your blood platelet count. You must have blood platelet counts done before you start Nplate, during Nplate
therapy, and after Nplate therapy is stopped.
See “What are the possible side effects of Nplate?” for other side effects of Nplate.
What is Nplate?
Nplate is a man-made protein medicine used to treat low blood platelet counts in adults with chronic immune
thrombocytopenia (ITP), when certain other medicines, or surgery to remove your spleen, have not worked well
enough.
Nplate is not for use in people with a precancerous condition called myelodysplastic syndrome (MDS) or low
platelet count caused by any condition other than chronic (lasting a long time) immune thrombocytopenia (ITP).
Nplate is only used if your low platelet count and medical condition increase your risk of bleeding.
Nplate is used to try to keep your platelet count about 50,000 per microliter in order to lower the risk for bleeding.
Nplate is not used to make your platelet count normal.
It is not known if Nplate works or if it is safe in people under the age of 18.
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What should I tell my healthcare provider before taking Nplate?
Tell your healthcare provider about all your medical conditions, including if you:
Have had surgery to remove your spleen (splenectomy). Have a bone marrow problem, including a blood cancer or MDS. Have or had a blood clot. Have chronic liver disease. Have bleeding problems. Have any other medical condition. Are pregnant, or plan to become pregnant. It is not known if Nplate will harm your unborn baby.
Pregnancy Surveillance Program: Women who become pregnant during Nplate treatment are encouraged to
enroll in Amgen’s Pregnancy Surveillance Program. The purpose of this program is to collect safety
information about the health of you and your baby. Contact the program as soon as you become aware of the
pregnancy, or ask your healthcare provider to contact the program for you. You or your healthcare provider can
get information and enroll in the program by calling 1-800-77-AMGEN (1-800-772-6436).
Are breast-feeding or plan to breast-feed. It is not known if Nplate passes into your breast milk. You and your
healthcare provider should decide whether you will take Nplate or breast-feed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription
medicines, vitamins, and herbal products. Know the medicines you take. Keep a list of them and show it to your
healthcare provider and pharmacist when you get a new medicine.
How should I take Nplate?
Before you receive Nplate you should first talk with your healthcare provider and understand the benefits and risks
of Nplate.
Nplate is given as a subcutaneous (SC) injection under the skin one time each week. You may not give Nplate
injections to yourself.
Your healthcare provider will check your platelet count every week and change your dose of Nplate as needed. This
will continue until your healthcare provider decides that your dose of Nplate can stay the same. After that, you will
need to have blood tests every month. When you stop receiving Nplate, you will need blood tests for at least
2 weeks to check if your platelet count drops too low.
Tell your healthcare provider about any bruising or bleeding that occurs while you are receiving Nplate.
If you miss a scheduled dose of Nplate, call your healthcare provider to arrange for your next dose as soon as
possible.
What should I avoid while receiving Nplate?
Avoid situations that may increase your risk of bleeding, such as missing a scheduled dose of Nplate. You should
arrange for your next dose as soon as possible and call your healthcare provider.
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What are the possible side effects of Nplate?
Nplate may cause serious side effects. See “What is the most important information I should know about
Nplate?”
The most common side effects of Nplate are:
Headache Pain in arms and legs
Joint pain Abdominal pain
Dizziness Shoulder pain
Trouble sleeping Indigestion
Muscle tenderness or weakness Tingling or numbness in hands and feet
People who take Nplate may have an increased risk of developing new or worsening changes in the bone marrow
called “increased reticulin.” These changes may improve if you stop taking Nplate. Your healthcare provider may
need to check your bone marrow for this problem during treatment with Nplate.
These are not all the possible side effects of Nplate. Tell your healthcare provider if you have any side effect that
bothers you or that does not go away. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 -800-FDA-1088.
You may also report side effects to Amgen at 1-800-77-AMGEN (1-800-772-6436).
General information about the safe and effective use of Nplate.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication
Guide summarizes the most important information about Nplate. If you would like more information, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for information about Nplate that is written
for health professionals.
What are the ingredients in Nplate?
Active ingredient: romiplostim Inactive ingredients: L-histidine, sucrose, mannitol, polysorbate 20, and hydrochloric acid
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Nplate®
(romiplostim) Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
U.S. License No. 1080
Revised: 04/2016 Patent: http://pat.amgen.com/nplate/
© 2008-2016 Amgen Inc. All rights reserved. www.nplate.com
1xxxxxx
vX
Reference ID: 3919389
3